A quadruplet regimen for treating transplant-ineligible, newly diagnosed multiple myeloma (MM), combining the oral drug ixazomib with daratumumab, lower-dose lenalidomide, and dexamethasone (Dara-RId), shows notable improvements in tolerability, with important reductions in neutropenia and peripheral neuropathy vs other quadruplet regimens, new research shows.

“Dara-RId offers a regimen that has the efficacy of a four-drug combination with the convenience of oral ixazomib, minimizing the risk of peripheral neuropathy for older, transplant ineligible newly diagnosed MM,” said first author Andrew J. Yee, MD, an assistant professor of medicine at Massachusetts General Hospital Cancer Center, Boston, in presenting the findings at the International Myeloma Society’s 2025 annual meeting in Toronto in mid-September. 

Patients with newly diagnosed MM are often not eligible for transplant when age or frailty reduce their tolerability to treatment toxicities, and while recent quadruple therapy regimens have shown encouraging improvements in progression-free survival, some patients still do not respond.

To explore a potentially improved quadruplet treatment regimen, Yee and his colleagues conducted the multicenter, phase 2 Alliance Foundation Trial 41, involving some key modifications from previous regimens, including the reduction of the dose of lenalidomide from 25 mg to 15 mg and replacement of the proteasome inhibitor bortezomib with oral ixazomib.

The inclusion of ixazomib offers several key advantages, including the oral formulation immediately being more patient friendly — patients do not have to come into clinic as often to receive this therapy, “and, being an oral medication, it also allows for extended therapy,” Yee explained.

In addition, ixazomib has a significantly reduced risk for peripheral neuropathy compared with the commonly used bortezomib.

“This is particularly meaningful for older, frailer patients, who may be more prone to falls,” he emphasized. 

For the study, 79 transplant-ineligible or deferred patients with newly diagnosed MM were enrolled at seven sites in the US between October 2020 and December 2023.

All patients received induction with 12 cycles of the regimen: subcutaneous daratumumab 1800 mg and oral lenalidomide 15 mg on days 1 through 21; oral ixazomib 4 mg on days 1, 8, 15; and dexamethasone weekly. Each cycle was 28 days. 

Following the 12 cycles, patients received maintenance with either Dara-RId or lenalidomide, based on prior randomization, for up to 2 years, with lenalidomide reduced to 10 mg and ixazomib reduced to 3 mg during the maintenance period.

The patients had a median age of 74, with nearly half (45.6%) aged 75 or older; 59% were female; and 83.5% were White. Approximately 40% of patients were considered to be frail.

At baseline, 41.8% of patients had International Staging System (ISS) stage I cancer, 35.4% had stage II, and 22.8% had stage III, with high-risk features in 37% by stage III and/or high-risk FISH.

In terms of outcomes during induction, the objective response rate was 92.4% and the partial response rate was 22.8%. Very good partial response occurred in 46.8%, complete response in 15.2%, and stringent complete response in 7.6%.

After 12 cycles of Dara-RId, the rate of progression-free survival was 92% and the overall survival rate was 93.6%.

Similar outcomes were observed between standard-risk and high-risk patients, as defined by the trial.

Older Age Key to Worse Outcomes?

Of note, the 12-month progression-free survival rate was 95.4% in those who were not considered frail, based on their simplified frailty score, compared with 87.2% in those who were frail. 

Likewise, the progression-free survival rate was higher among patients who were under 80 and nonfrail (95.4%) compared with those who were over 80 (all frail, by definition; 72.7%).

“Frail patients tend to have early progression events, though age over 80 may be a more important factor with induction outcomes,” Yee said.

Adverse events with the regimen were generally consistent with those observed with other quadruplet therapies, with grade 3 or higher neutropenia occurring in 16.5% of patients, infections in 11.4%, and anemia in 10.1%.

Furthermore, there were no reports of grade 3 or higher neuropathy (grade 1, 15%; grade 2, 14%).

Of note, no treatment-related deaths were reported, with 61 patients going on to maintenance therapy and seven patients discontinuing treatment for adverse events during induction.

Improvements vs Other Quadruplet Trials

As expected, frail patients tended to have more dose reductions of lenalidomide and ixazomib vs nonfrail patients; however, the overall tolerability was encouraging, Yee said.

“It should be emphasized that there is improved tolerability compared with what we see with other regimens,” he noted.

“In particular, the rate of grade 3 neutropenia in our study was about 17%, which is significantly lower than in the other regimens that we have heard about, and I think this is probably due to the lower dose of lenalidomide used in the study. Moreover, there was a significantly reduced rate of peripheral neuropathy with the use of ixazomib, including all-grade neuropathy and in particular grade 3 or higher neuropathy.”

Yee pointed out, “Any neuropathy is an adverse event to avoid, but especially in our older frailer patients, who are more prone to falls.” 

Specifically, rates of grade 3 or higher neutropenia (16.5% in the current study) were 44.2% and 50% in the Dara-VRd CEPHEUS and Dara-Rd MAIA quadruplet trials, respectively. 

Peripheral neuropathy of any grade or of grade 3 or above, at 29% and 0%, respectively, in the current trial, were comparatively 61.9% and 11.2% in the CEPHEUS trial.

Commenting on the study prior to its presentation, Hira Mian, MD, the myeloma lead at the Juravinski Cancer Centre and associate professor at McMaster University, in Hamilton, Ontario, Canada, said the need to improve outcomes and tolerability in transplant-ineligible patients is a key challenge.

“We know that transplant-ineligible patients with multiple myeloma represent a large proportion of newly diagnosed myeloma patients, and it’s a heterogeneous group of patients whose outcomes are impacted by the frailty spectrum — even with novel therapies,” she said.

While “tremendous progress” has been made in recent years, allowing patients to live longer, “the key question for the next new treatment for transplant-ineligible newly diagnosed patients with MM is: Can we get the same or better efficacy with reduced toxicity as well as a reduced burden of treatment?” Mian said.

Further commenting on the trial in a meeting overview, Marc S. Raab, MD, a professor of medicine and director of the Heidelberg Myeloma Center, Department of Internal Medicine V at Heidelberg University Hospital & German Cancer Research Center, in Heidelberg, Germany, noted the key findings regarding frailty and age.

“What I think is interesting is that it first looks like the frail patients actually did not do as well as the nonfrail patients in this patient group; however, when they looked more closely, it was actually the patients above 80 years of age that did not fare as well compared to the other frail patients below the age of 80,” Raab said. 

“So that might be an important message to keep in mind in designing future trials, that consider specific patient populations, such as those with frailty.” 

Yee noted that findings represent early preliminary data. Further study outcomes from the maintenance arm, and the depth of responses by minimal residual disease, are pending.

The study was funded by Alliance Foundation Trials, Bristol Myers Squibb (BMS), Johnson & Johnson, and Takeda. Yee reports relationships with AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda. Mian discloses ties with BMS, Takeda, Johnson & Johnson, Amgen, Sanofi, Forus, GSK, and Pfizer. Raab reports relationships with BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie, Oncopeptides, and Takeda.